Non-squamous Non-small Cell Lung Cancer Research Articles

Bevacizumab for Brain Radiation Necrosis in Patients With Nonsquamous Nonsmall Cell Lung Cancer

IntroductionRecent advances in therapies based on molecular targeted agents and immune checkpoint inhibitors have prolonged the survival of non–small cell lung cancer (NSCLC) patients and increased the number of such patients undergoing radiotherapy for brain metastases. Brain radiation necrosis, a late adverse event of radiotherapy, occurs in ∼10% of these latter individuals. Whereas bevacizumab has shown efficacy for brain radiation necrosis, optimal treatment strategies have remained elusive. We here assessed the efficacy of bevacizumab for brain radiation necrosis in NSCLC patients. Patients and MethodsIn this retrospective study, we evaluated NSCLC patients treated with bevacizumab for brain radiation necrosis diagnosed on the basis of MRI or [11C]methionine-PET. The volumes of radiation necrosis and peripheral edema were measured. ResultsFour NSCLC patients were treated with bevacizumab for brain radiation necrosis. All four patients manifested neurological symptoms with radiation necrosis accompanied by peripheral edema. Histological analysis showed adenocarcinoma in all patients, with two harboring EGFR mutations, one a HER2 mutation, and one a KRAS mutation. The median radiation dose was 24 Gy, median time from radiation to bevacizumab treatment was 27 months, and median time from the start of bevacizumab treatment to radiological improvement was 5 weeks. Neurological symptoms improved in two of the four patients, and the dose of dexamethasone was reduced in three patients. The volumes of necrosis and peripheral edema in each patient were noticeably reduced by bevacizumab treatment. ConclusionBevacizumab is an effective treatment for brain radiation necrosis in patients with nonsquamous NSCLC.

PP01.53 Patient-Reported Outcomes (PROs) in Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC): PERLA Trial Comparing First-Line Chemotherapy Plus Dostarlimab or Pembrolizumab

PP01.53 Patient-Reported Outcomes (PROs) in Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC): PERLA Trial Comparing First-Line Chemotherapy Plus Dostarlimab or Pembrolizumab

PPD01.07 Phase 2 Trial of Mecbotamab Vedotin (BA3011), a CAB-AXL-ADC, Alone or in Combination With Nivolumab in Patients With Non-Squamous NSCLC

PPD01.07 Phase 2 Trial of Mecbotamab Vedotin (BA3011), a CAB-AXL-ADC, Alone or in Combination With Nivolumab in Patients With Non-Squamous NSCLC

Cost-effectiveness of large-panel next-generation sequencing in guiding first-line treatment decisions for patients with nonsquamous advanced non-small cell lung cancer.

Clinical practice guidelines recommend broad-panel genomic profiling to identify actionable genomic alterations for patients with advanced non-small cell lung cancer (aNSCLC). To assess the cost-effectiveness of large-panel next-generation sequencing (LP-NGS) compared with current empirical single-gene test (SGT) patterns to inform first-line treatment decisions for patients with aNSCLC from a US commercial payer perspective, accounting for the effect of testing turnaround time and time to treatment initiation. We developed a discrete-event simulation model to estimate the impact of LP-NGS vs SGT for patients with nonsquamous aNSCLC. Discrete events and timing included testing patterns, receipt of the initial test result, treatment initiation (targeted vs nontargeted therapies), switching, retesting, rebiopsies, clinical trial participation, progression on therapy, and death. LP-NGS and SGT cohorts each comprised 100,000 adults with aNSCLC simulated over a 5-year postdiagnosis period, assumed to have the same distribution of genomic alterations. The model predicted the proportion of patients receiving appropriate first-line therapy according to clinical practice guidelines. Economic outcomes included expected life-years gained, quality-adjusted life-years, and the total costs of care over 5 years. Sensitivity and scenario analyses explored the robustness of the base-case model results. In the base-case model, LP-NGS was likely to identify more alterations than SGT. Total 5-year costs per patient were $539,658 for LP-NGS and $544,550 for SGT (net difference, $4,892 lower costs per patient for LP-NGS), which is likely to be cost-effective 95.1% of the time. The most influential model parameters on the 5-year total costs of care were preprogression nondrug medical costs on nontargeted therapy, NGS turnaround time, and clinical trial participation. This study suggests that LP-NGS to guide first-line treatment decisions is clinically more appropriate (more likely to identify alterations and subsequently allocate patients to clinically appropriate therapy) and provides a dominant cost-effectiveness treatment strategy over 5 years for patients with newly diagnosed aNSCLC in the United States.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study

BackgroundCadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. Trial designThis single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. ResultsThe study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

PP01.88 REZILIENT3: Phase 3 Study of Zipalertinib plus Chemotherapy in Previously Untreated, Advanced Nonsquamous NSCLC Patients with EGFR Exon 20 Insertions

PP01.88 REZILIENT3: Phase 3 Study of Zipalertinib plus Chemotherapy in Previously Untreated, Advanced Nonsquamous NSCLC Patients with EGFR Exon 20 Insertions

Pathologic Response and Survival after Neoadjuvant Chemotherapy with Bevacizumab Followed by Surgery for Clinical Stage II/IIIA Nonsquamous Non-Small-Cell Lung Cancer: Results from a Phase II Feasibility Study (NAVAL).

The objective of this study was to evaluate the relationship between pathologic response and survival in patients with clinical stage II/IIIA nonsquamous non-small-cell lung cancer (NSCLC) who intended to undergo neoadjuvant chemotherapy with bevacizumab, followed by surgery. In this phase II NAVAL study evaluating the feasibility of neoadjuvant chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg), followed by surgery, progression-free survival (PFS) and overall survival (OS) were assessed as the secondary endpoints. Patients were categorized based on the proportion of residual viable primary tumor in the resected specimen after neoadjuvant chemotherapy: those with residual tumor in less than one-third were classified as pathologic responders, the rest as nonresponders. Of the 30 patients, 25 underwent surgical resection after three cycles of neoadjuvant chemotherapy with bevacizumab; 5 did not undergo surgery. Among all 30 patients, the rates of 2- and 5-year PFS were 41.5% and 34.6%, respectively, and the rates of 2- and 5-year OS were 70.0% and 60.0%, respectively. A total of 6 patients (20%) were classified as pathologic responders; the other 24 (80%), as nonresponders. The five-year PFS differed significantly between pathologic responders (100%) and nonresponders (17.5%; p = 0.002). The five-year OS also differed significantly between pathologic responders (100%) and nonresponders (43.5%; p = 0.006). Pathologic response seems to be a predictor of survival. Long-term survival after surgery is expected for pathologic responders, whereas additional therapy is needed for nonresponders.

EE203 Number Needed to Treat and Cost of Preventing an Event Analysis for Pembrolizumab in Non-Squamous Metastatic Non-Small Cell Lung Cancer in Colombia

EE203 Number Needed to Treat and Cost of Preventing an Event Analysis for Pembrolizumab in Non-Squamous Metastatic Non-Small Cell Lung Cancer in Colombia

PT35 Cost-Effectiveness Analysis of Nivolumab Versus Docetaxel for the Treatment of Advanced Nonsquamous NSCLC Including PD-L1 Testing in the United States

PT35 Cost-Effectiveness Analysis of Nivolumab Versus Docetaxel for the Treatment of Advanced Nonsquamous NSCLC Including PD-L1 Testing in the United States

Efficacy and safety of bevacizumab and platinum‑based chemotherapy as neoadjuvant regimen for stage‑IIIA non‑squamous non‑small cell lung cancer: A retrospective study.

Bevacizumab plus platinum-based chemotherapy provides modest benefits in non-squamous non-small cell lung cancer (NSCLC), while its application as a neoadjuvant regimen has yet to be validated. The present study aimed to assess the efficacy of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with stage-IIIA non-squamous NSCLC. Data from 110 patients with stage-IIIA non-squamous NSCLC with negative driver genes, who received neoadjuvant bevacizumab plus platinum-based chemotherapy (n=50) or neoadjuvant platinum-based chemotherapy alone (n=60), and tumor resection, were retrospectively reviewed in the current study. In addition, the data on pathological response, disease-free survival (DFS), overall survival (OS) and adverse events were obtained. The results demonstrated that neoadjuvant bevacizumab plus chemotherapy did not significantly increase the pathological complete response (pCR) rate in comparison with neoadjuvant chemotherapy alone (18.0 vs. 8.3%; P=0.130). However, neoadjuvant bevacizumab plus chemotherapy significantly increased the rates of DFS (P=0.007) and OS (P=0.049) compared with neoadjuvant chemotherapy alone. Adjustments were then performed using multivariate logistic or Cox regression analyses, which demonstrated that neoadjuvant bevacizumab plus chemotherapy in comparison with neoadjuvant chemotherapy alone only significantly independently prolonged DFS [hazard ratio (HR)=0.251; P=0.042], but did not significantly affect pCR (odds ratio=2.897; P=0.117) or OS (HR=0.297; P=0.158). Furthermore, no significant differences were demonstrated between the number of adverse events in patients receiving neoadjuvant bevacizumab plus chemotherapy in comparison with those receiving neoadjuvant chemotherapy alone (all P>0.05). In conclusion, neoadjuvant bevacizumab plus platinum-based chemotherapy was only associated with a significant improvement in the rate of DFS, but showed limited efficacy in improving pCR and OS rates in comparison with neoadjuvant chemotherapy alone in patients with stage-IIIA non-squamous NSCLC. Therefore, a larger sample size and randomized controlled studies are needed for further validation of the findings of the present study.

Advanced non-squamous NSCLC with no actionable oncogenic driver in Spain: a cross-sectional descriptive analysis of data from the Thoracic Tumor Registry.

Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. According to their histology, most NSCLCs are considered non-squamous cell carcinoma (NSCC), and up to 85% of the latter may lack either one of the two main actionable oncogenic drivers (i.e., EGFR mutations and ALK rearrangements). Our analysis aimed to describe the clinical and epidemiological characteristics of Spanish patients suffering from NSCC with no actionable oncogenic driver in daily clinical practice. A retrospective, cross-sectional, descriptive analysis. We analyzed the records of all Spanish patients with advanced NSCC diagnosed between January 2011 and January 2020 and included in the Spanish Thoracic Tumor Registry database. We evaluated the presence of metastasis and molecular profiling at the time of diagnosis and treatments received. We also assessed overall survival (OS) and progression-free survival (PFS) according to first-line treatment. One thousand seven hundred ninety-seven Spanish patients with NSCC were included. They were mainly men (73.2%), smokers (current [44.4%] and former [44.4%]) and presented adenocarcinoma histology (97.6%). Most patients had at least one comorbidity (80.4%) and one metastatic site (96.8%), and a non-negligible number of those tested were PD-L1 positive (35.2%). Notably, the presence of liver metastasis indicated a shorter median OS and PFS than metastasis in other locations (p < 0.001). Chemotherapy was more often prescribed than immunotherapy as first-, second-, and third-line treatment in that period. In first-line, the OS rates were similar in patients receiving either regimen, but PFS rates significantly better in patients treated with immunotherapy (p = 0.026). Also, a high number of patients did not reach second- and third-line treatment, suggesting the failure of current early diagnostic measures and therapies. This analysis of the most lethal tumor in Spain could highlight the strengths and the weaknesses of its clinical management and set the ground for further advances and research.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]

Beamion LUNG-2: A phase III randomized controlled trial of zongertinib (BI 1810631) versus standard of care (SoC) in patients with locally advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) mutations.

TPS8654 Background: HER2mutations are present in 2–4% of NSCLC tumors, and ~50% occur in the TKD. First-line SoC for patients with HER2mutation-positive (m+) NSCLC is platinum-based chemotherapy ± immunotherapy; however, no targeted first-line treatment has been approved. Zongertinib is a HER2-selective tyrosine kinase inhibitor (TKI) that binds to both wild-type and mutated HER2 but spares EGFR. In a Phase Ia trial in 53 pre-treated patients with HER2 aberration-positive solid tumors, zongertinib conferred an objective response (OR)/disease control rate (DCR) of 49/91% and an OR/DCR of 58/97% in those patients with HER2m+ NSCLC (n=36), with manageable safety with few EGFR-associated toxicities (Beamion LUNG-1; NCT04886804). Here, we describe Beamion LUNG-2 (NCT06151574), a Phase III, randomized, active-controlled, open-label trial designed to assess the efficacy of first-line zongertinib versus SoC in patients with HER2m+, locally advanced or metastatic non-squamous NSCLC. Methods: Approximately 270 patients from ~160 sites across 30 countries will be randomized 1:1 to receive either zongertinib or SoC and stratified by the presence of the A775_G77insYVMA HER2 mutation. In the experimental treatment arm, patients will receive 120 mg oral zongertinib once-daily in 21-day cycles. In the comparator treatment arm, patients will receive 500 mg/m2 intravenous pemetrexed chemotherapy, plus either 75 mg/m2 cisplatin or Area Under the Curve 5 carboplatin, plus 200 mg pembrolizumab on Day 1 once every 3 weeks (q3w) for four 21-day cycles, then maintenance with 500 mg/m2 pemetrexed plus 200 mg pembrolizumab q3w for up to 35 cycles. Treatment in both arms will continue until progressive disease (PD; RECIST 1.1), undue toxicity, or other criteria are met. The primary endpoint is progression-free survival (RECIST 1.1), by blinded central independent review. Secondary endpoints include OR (defined as best overall response of complete or partial response, RECIST 1.1); patient-reported outcomes analysed as changes from baseline to Week 25; overall survival and occurrence of adverse events (CTCAE version 5.0). Key inclusion criteria are histologically or cytologically diagnosed advanced and/or metastatic non-squamous NSCLC; ≥1 measurable lesion (RECIST 1.1); no prior systemic treatment for locally advanced or metastatic disease; a documented HER2 TKD mutation; and eligibility to receive the selected SoC. Key exclusion criteria are tumors with targetable alterations with an available treatment; presence/history of uncontrolled/symptomatic leptomeningeal disease; and radiotherapy or major surgery ≤4 weeks prior to randomization. Clinical trial information: NCT06151574 .

A phase 1b, multicenter, open-label study of valemetostat in combination with DXd antibody drug conjugates (ADCs), trastuzumab deruxtecan (T-DXd) or datopotamab deruxtecan (Dato-DXd), in patients with solid tumors.

TPS4180 Background: Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1. Valemetostat 200 mg PO QD has demonstrated clinical efficacy and favorable tolerability in multiple hematologic malignancies. EZH2 controls gene expression, including the expression of genes involved in DNA damage response, like DNA/RNA helicase Schlafen 11 ( SLFN11). In response to DNA damage, SLFN11 binds to chromatin, causing a replication block and inducing apoptosis. Expression levels of SLFN11 indicate sensitivity to DNA-damaging agents (DDAs) in various solid tumors and are downregulated in chemotherapy-resistant tumor cells due to trimethylation of H3K27 at the SLFN11 gene locus. EZH2 inhibition by valemetostat is expected to upregulate SLFN11 and sensitize tumor cells to DDAs. Topoisomerase inhibition causes DNA strand breaks, which may synergize with valemetostat. This study will combine valemetostat with topoisomerase-I inhibitor ADCs, T-DXd or Dato-DXd, for the first time in patients (pts) with HER2-positive (HER2+) gastric cancer (GC) and non-squamous non-small-cell lung cancer (NSCLC), respectively. T-DXd is globally approved for the treatment of pts with locally advanced or metastatic HER2+ GC and other cancers, having received prior anti-HER2–based treatment. In the phase 3 TROPION-Lung01 trial, Dato-DXd significantly improved progression-free survival (PFS) vs standard chemotherapy in previously treated, locally advanced or metastatic NSCLC. Methods: This global, phase 1b, multicenter, two-part, open-label study is structured as a Master Protocol with independent sub-protocols defined by disease and treatment combination, including valemetostat + T-DXd in pts with 2L+ advanced or metastatic HER2+ GC or gastro-esophageal junction adenocarcinoma, and valemetostat + Dato-DXd in pts with 2L+ locally advanced, unresectable, or metastatic non-squamous NSCLC. Target enrollment is 70 pts per sub-protocol across 35 sites in US and Japan. Part 1 will determine the valemetostat recommended dose for expansion (RDE), combining escalating doses of valemetostat 50–200 mg PO QD with T-DXd at 5.4 mg/kg or 6.4 mg/kg (dose after first escalation) IV Q3W (GC protocol), or with fixed dose Dato-DXd 6.0 mg/kg IV Q3W (NSCLC protocol). Part 2 will evaluate the efficacy of valemetostat QD + Dato-DXd or T-DXd at the RDE. The main eligibility criteria for both protocols include at least 1 measurable lesion (per RECIST v1.1), an ECOG PS score of 0–1, and adequate organ function. Primary endpoints of this study are safety and tolerability of valemetostat in Part 1 and objective response rate in Part 2. Secondary endpoints include duration of response, PFS, overall survival and pharmacokinetics. Clinical trial information: NCT06244485 .

Effect of first-line bevacizumab on prognosis of second or later-line immunotherapy in patients with advanced non-squamous non-small cell lung cancer: A retrospective analysis.

e20570 Background: Previous studies have demonstrated that anti-angiogenic agents have the capacity to regulate tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). However, the impact of previous anti-angiogenic agents on clinical outcomes of non-squamous non-small cell lung cancer (nsqNSCLC) patients treated with ICIs remains unclear. Methods: In the present study, we incorporated POPLAR, OAK, and BIRCH trials with a total of 912 non-squamous NSCLC patients. Using Vivli data-sharing platform, we have obtained specific clinical information about individual patients. The progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier analysis with a log-rank test, and the corresponding hazard ratio (HR) and 95% confidence interval (CI) were estimated using the Cox proportional regression model. Chi-squared test was used to compare proportions between different groups. All statistical analysis and plotting were done in R version 4.1.1 and SPSS R26.0.0.2. P less than 0.05 was considered statistically significant. Results: In the overall cohort, PFS (2.77 months vs. 2.83 months; hazard ratio [HR],1.1; 95% confidence interval [CI], 0.9 to 1.3; p = 0.43) and OS (15.1 months vs. 14.3 months; HR,1.0; 95% CI, 0.8 to 1.3; p = 0.86) in patients treated with bevacizumab before atezolizumab (pre-bevacizumab group) and patients treated without bevacizumab before atezolizumab (no pre-bevacizumab group) were not statistically different. Merely in patients with KRAS mutation, no pre-bevacizumab group had an improved PFS (4.04 months vs. 1.64 months; HR,1.7; 95% CI, 1.0 to 2.7; p = 0.04) as compared to the pre-bevacizumab group. Longer use of bevacizumab (≥1.43 months) before atezolizumab suggested a longer PFS compared with shorter use of bevacizumab ( &lt; 1.43 months) (20.07 months vs. 2.75 months; HR,0.40; 95% CI, 0.17 to 0.95; p = 0.03). Conclusions: In conclusion, our study demonstrated that whether or not first-line bevacizumab is given has no effect on PFS or OS of second-line or later-line immunotherapies. Patients with longer duration of first-line bevacizumab use have a longer PFS on later immunotherapy. The more appropriate timing and sequence of administration of anti-angiogenic agents and ICIs will help us achieve a better therapeutic effect in the clinical practice of patients with advanced NSCLC.

Five-year survival outcomes from the PIT-1 trial: Pemetrexed-cisplatin plus bevacizumab or concurrent thoracic radiation therapy followed by surgery in stage IIIA (N2) nonsquamous non-small cell lung cancer.

8064 Background: Personized Induction Therapy-1 (PIT-1) is a multicenter, randomized phase II selection design trial of pemetrexed-cisplatin plus bevacizumab (BEV arm) or concurrent thoracic radiation therapy (TRT arm) followed by surgery in patients with stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC). The TRT arm was chosen as the investigational induction treatment strategy for a future phase III study based on the results of a numerically higher 2-year progression-free survival (PFS, primary endpoint) in the TRT arm and fatal postoperative complications observed only in the BEV arm. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. Methods: Patients with stage IIIA (N2) nonsquamous NSCLC were randomly assigned (1:1) induction therapy consisting of pemetrexed and cisplatin plus bevacizumab (n = 44) or concurrent TRT (n = 44) followed by surgery. Among them, 38 patients in the BEV arm and 37 patients in the TRT arm underwent surgery. Five-year overall survival (OS), 5-year PFS, and patterns of postoperative recurrence were compared between arms. Prognostic factors of OS were analyzed in surgically resected patients using Cox’s proportional hazard model. Results: The median follow-up was 66.4 months. In 82 treated patients, the 5-year OS and PFS rates were 63.5% (95% CI: 46.9-76.1) and 26.2% (95% CI: 14.1-40.0) in the BEV arm (n = 42), and 57.2% (95% CI: 40.5-70.8) and 27.5% (95% CI: 14.9-41.7) in the TRT arm (n = 40), respectively. There were no statistical differences in OS ( P = 0.572) and PFS ( P = 0.356). In 75 surgically resected patients, pathological nodal down stage was the only significant prognostic factor of OS ( P = 0.014). Age, sex, smoking status, clinical T stage, clinical N stage based on a computed tomography scan, preoperative serum CEA and CYFRA level, EGFR mutation status, pathological complete response, and major pathological response did not have a significant prognostic impact on OS. The patterns of postoperative recurrence were different between arms: locoregional only, in four (11%) and one (3%); distant metastasis only, in 16 (42%) and 21 (57%); and both, in five (13%) and four (11%) in the BEV and TRT arms, respectively. The recurrence rate of ipsilateral hilar or mediastinal lymph nodes (the irradiation field) was significantly lower in the TRT arm (3%) than in the BEV arm (21%, P= 0.01). Conclusions: Five-year survival outcomes were not different between the BEV and TRT arms. The TRT arm demonstrated sufficient local control, but insufficient control of distant metastasis so this is an important issue that requires improvement in the future. Clinical trial information: s031180402.

Cost-efficiency and expanded access modeling of toripalimab versus pembrolizumab in locally advanced or metastatic nonsquamous non-small cell lung cancer.

e20590 Background: Toripalimab, a novel anti-PD-1 antibody, demonstrated significant PFS and OS benefit in combination with pemetrexed and platinum (toripalimab+PemPlat) in advanced nonsquamous non-small cell lung cancer (nsNSCLC) over placebo+PemPlat in the CHOICE-01 trial (median PFS: 9.7 vs 5.5 months; median OS: NE vs 17.0 months), though not currently approved for this indication. FDA-approved pembrolizumab+PemPlat was similarly found to extend PFS and OS over placebo+PemPlat in metastatic nsNSCLC patients in KEYNOTE-189 (median PFS: 9.0 vs 4.9 months; median OS: 22.0 vs 10.7 months). The current wholesale acquisition cost (WAC) of pembrolizumab is $11,115 per dose. The WAC of toripalimab, recently approved for nasopharyngeal carcinoma, is 80% of pembrolizumab. In this simulation we modeled the cost-efficiency of the toripalimab regimen versus pembrolizumab in nsNSCLC and the budget-neutral expanded access to additional toripalimab enabled by savings. Methods: Utilizing WAC drug costs and treatment administration costs, we estimated the cost-efficiency of the toripalimab regimen for the median PFS 9.7 months observed in CHOICE-01 versus the pembrolizumab regimen for the median PFS 9.0 months observed in KEYNOTE-189. We assumed that 14 cycles of toripalimab+Pem (with carboplatin in cycles 1-4) are administered over 9.7 months and 13 cycles of pembrolizumab+Pem (with carboplatin in cycles 1-4) are administered over 9.0 months. From the differential, we estimated the potential expanded access to additional toripalimab treatment on a budget-neutral basis. The model was replicated utilizing an ex ante toripalimab average sales price (ASP) of 80% of pembrolizumab ASP. Results: The pembrolizumab regimen costs $176,705 over 9.0 months (13 cycles) while the toripalimab regimen costs $159,136 over 9.7 months (14 cycles) at the respective WACs, for savings of $17,569 per patient. This would enable the purchase of 1.6 additional toripalimab+pemetrexed maintenance cycles on a budget-neutral basis for every patient treated. For every 9 patients treated with toripalimab instead of pembrolizumab, one additional patient could be treated with the full toripalimab regimen (all agents) for 9.7 months. Extrapolated to the US incident nsNSCLC population of 49,647 patients, if only 5% of patients are treated with toripalimab instead of pembrolizumab estimated savings of $43,611,849 provide access to 3,849 additional toripalimab+pemetrexed maintenance cycles or 274 full toripalimab regimens (all agents for 9.7 months) budget-neutrally. Similar results were seen in the ex ante ASP model. Conclusions: If approved for use in advanced nsNSCLC, toripalimab is estimated, at its market-entry WAC, to save $17.6 thousand per patient over a median PFS 9.7 months treatment duration compared to the pembrolizumab regimen over a median PFS 9.0 months of treatment.

Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.

8568 Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]

Comparison and performance of three plasma next-generation sequencing assays versus tissue testing for the detection of actionable driver mutations in advanced non-squamous non-small cell lung carcinoma.

e20018 Background: Liquid biopsy (LB) is a useful tool for the detection of actionable mutations in advanced non-squamous non-small cell lung cancer (NS-NSCLC) at progression. However, the clinical benefits of integrating both LB and tissue biopsy (TB)-based genomic profiling at diagnosis of NS-NSCLC remain uncertain. Methods: We tested three commercially available next-generation sequencing (NGS) gene panel assays in circulating cell-free DNA (cfDNA) using replicate sets of 85 LB samples from advanced NS-NSCLC patients at baseline and compared the results with matched TB for the detection of tier IA/B (AMP/ASCO/CAP classification) alterations. We used methylation testing of cfDNA to assess the tumor fraction (TF). We correlated molecular data with clinico-pathological features and follow-up data. Results: All TB-based NGS results were interpretable. 5 LB-based NGS results for one assay were not performed due to the material exhaustion. Tier IA/B gene alteration was detected by LB-based NGS and TB-based NGS in 18 to 23 (21 to 27%) patients and in 35 (41%) patients, respectively. The positive percent agreement of each LB-based NGS assay method compared with TB-based NGS assay ranged from 51% to 68%. The incremental add provided by first LB-based NGS ranged from 0 to 23% versus 25 to 45% for first TB-based NGS, depending on the LB-based NGS assay. It includes one EGFR uncommon mutation, 9 MET amplifications and 2 HER2 amplifications detected by LB-based NGS assays that were not detected by TB-based NGS. Overall agreement between the three LB-based NGS assays was 44%. Hybrid-capture based assay detects 14 MET/HER2 CNVs, two METex14 skipping mutation and two ALK fusions that were not detected by amplicon-based assay. Amplicon-based assay detects one uncommon EGFR mutation, one KRAS non-G12C and one ALK fusion that were not detected by hybrid-capture based assay. 64 LB samples were tested for cfDNA methylation. Positive predictive value and negative predictive value of the detection of TF by cfDNA methylation profiling was 90% and 92%, respectively. The only false-negative result of TF evaluation by cfDNA methylation profiling was observed for a variant with a cfDNA VAF &lt; 1%. Correlation analyses with clinicopathological data are ongoing. Conclusions: While concordance with tissue is relatively high, the incremental add provided by LB-based NGS at diagnosis of advanced NS-NSCLC compared to TB-based NGS is limited and greatly varies according to the sequencing method used. Thus, LB-based NGS at diagnosis of NSCLC can be used as a complement of TB-based NGS or as an alternative when tissue is not available.